PROJECT SUMMARY/ABSTRACT ?Designer drugs? burst onto the United States (US) recreational drug market in early 2009. By 2011, ?bath salts,? which are most often mixtures of synthetic cathinones and other drugs such as caffeine, were linked to numerous press reports of bizarre and violent behavior, and accounted for well over 20,000 emergency room visits. Over the nearly 10 years since their introduction, the number of synthetic cathinones available for use has grown from 3 (MDPV, methylone, and mephedrone) to over 140. Based on work from our lab and others, we now know that the reinforcing effects of cathinones exist on a continuum, with drugs such as methylone functioning as relatively modest reinforcers (cocaine>methylone), and drugs such as MDPV, and ?-PVP functioning as exceptionally powerful reinforcers capable of maintaining significantly greater levels of responding than either cocaine or methamphetamine. In addition evidence to show that the reinforcing effectiveness of cocaine and synthetic cathinones, such as MDPV and ?-PVP, is directly related to their selectivity for DAT over SERT, our laboratory has also shown that these reinforcing (and toxic) effects can be synergistically enhanced when drugs such as MDPV and methylone are administered in combination with other ?bath salts? constituents, such as caffeine. In the last 5 years, we have learned a great deal about the pharmacology and abuse-related effects of synthetic cathinones; however, over this same time the synthetic drug market and the landscape of recreational drug use more broadly have changed dramatically. In 2013, heroin began to supplant prescription opioids as opioid users? drug of choice; by 2014, synthetic opioids, mainly fentanyl, had flooded the market. These changes coincided with a doubling of the incidence of opioid-related deaths, from ~25,000 in 2013 to >47,000 in 2017, over half of which (~28,000) were linked to synthetic opioids, such as fentanyl. Over this same time, overdose deaths related to stimulants (e.g., cocaine, methamphetamine and synthetic cathinones), have more than doubled over the same time from fewer than 10,000 in 2013, to over 24,000 in 2017. Moreover, it is becoming increasingly clear that these two phenomena are not occurring in isolation, with ~50% of opioid-related deaths involving stimulants, and ~50% of stimulant-related deaths also involving opioids. Thus, the US is in the midst of a polysubstance abuse epidemic, the effects of which are increasing at an exponential rate. This research project aims to 1) determine the impact of self-administration of ?-PVP during adolescence on the development of compulsive drug taking and vulnerability to opioid abuse later in life; 2) characterize the interactions between the abuse-related and toxic effects of stimulants and opioids; and 3) examine the degree to which opioid dependence and withdrawal impact the nature of the interactions between the abuse-related and toxic effects of mixtures of stimulants and opioids. Together, these studies will provide essential information about the complexities associated with the co-use of multiple substances from different pharmacological classes that will advance efforts to develop novel and effective treatments for abuse-related and toxic effects of polysubstance abuse.